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The N E W E N G L A N D J O U R N A L of M E D I C I N E

The N E W E N G L A N D J O U R N A L of M E D I C I N E. ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24. Effect of Rosiglitazone on the Risk of Myocardial Infarction

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The N E W E N G L A N D J O U R N A L of M E D I C I N E

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  1. TheNEW ENGLAND JOURNALofMEDICINE ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24 Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. CONCLUSIONS Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death…that had borderline significance.

  2. Rosiglitazone and Cardiovascular Events Myocardial Infarction 27,833 Patients 158 Events 42 Trials 15,470 12,205 No Event 86 72 MI Rosiglitazone Control 0.59% 0.55% Event Rate

  3. 3000 2000 1000 0 Patients No Event N=38 MI Rosiglitazone Control Zero event trials 4 4 EXCLUDED Rosiglitazone and Cardiovascular Events Myocardial Infarction

  4. 3000 2000 1000 0 Patients No Event N=23 Death Rosiglitazone Control Zero event trials 19 19 EXCLUDED Rosiglitazone and Cardiovascular Events Cardiovascular Death

  5. Rosiglitazone and Cardiovascular Events Peto Meta-Analysis Myocardial Infarction Cardiovascular Death 1 Odds Ratio Odds Ratio 1.43 (1.03-1.98) p=0.03 N=38 1.64 (0.98-2.14) p=0.06 N=23

  6. 3000 2000 1000 0 Patients No Event MI Rosiglitazone Control Zero event cells 6 20 INCLUDED Rosiglitazone and Cardiovascular Events Myocardial Infarction

  7. 3000 2000 1000 0 Patients No Event Death Rosiglitazone Control Zero event cells 2 15 INCLUDED Rosiglitazone and Cardiovascular Events Cardiovascular Death

  8. Rosiglitazone and Cardiovascular Events Impact of Zero Events on Peto’s Odds Ratio

  9. 3000 2000 1000 0 Patients No Event Death Rosiglitazone Control Rosiglitazone and Cardiovascular Events Cardiovascular Death

  10. 3000 2000 1000 0 Patients No Event Death k=1/2 k~1/N Rosiglitazone Control Rosiglitazone and Cardiovascular Events Continuity Correction Sweeting et al, What to add to nothing? Stat Med 2006;23:1351-75.

  11. * Rosiglitazone and Cardiovascular Events Meta-Analytic Sensitivity Myocardial Infarction Cardiovascular Death Peto ( - ) Inverse variance 1/N ( - ) Inverse variance 1/2 ( - ) Mantel-Haenszel 1/N ( - ) Mantel-Haenszel 1/2 ( - ) Mantel-Haenszel 1/N (+) Mantel-Haenszel 1/2 (+) Uniform Bayes 1/N (+) Uniform Bayes 1/2 (+) 0.5 1.0 1.5 2.0 2.5 3.0 0.5 1.0 1.5 2.0 2.5 3.0 Odds Ratio Odds Ratio

  12. Rosiglitazone and Cardiovascular Events Magnitude of Harm Myocardial Infarction Cardiovascular Death Uncorrected Uncorrected Probability of Harm Corrected Corrected Relative Risk Threshold Relative Risk Threshold

  13. Rosiglitazone and Cardiovascular Events Limitations of the Published Meta-Analysis • Not designed to assess outcomes • No central adjudication of events • No standardized definitions of events • Limited sample size • Short term duration • No patient level data • No sensitivity analysis • No continuity correction

  14. Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from CardiovascularCausesAlternative Interpretations of the Evidence Sanjay Kaul, MD; George A. Diamond, MD Division of Cardiology Cedars-Sinai Medical Center Los Angeles, California No conflicts to disclose

  15. Rosiglitazone and Cardiovascular Events Key Questions Regarding the Published Meta-Analysis • Are the risk estimates robust? • Is there heterogeneity? • - What is the impact of continuity corrections on clinically relevant subgroups? • Are the risk estimates consistent with other studies?

  16. Rosiglitazone and Cardiovascular Events Is There Heterogeneity? • Pooling justified due to lack of statistical heterogeneity • Cochran’s Q test of heterogeneity Limited ability to detect variability across studies with sparse data (low statistical power) Even if studies are statistically homogeneous there may be clinical heterogeneity in study design and population

  17. Meta-analysis N = 42 • Without diabetes (N = 3) • Alzheimer's (N = 1) • Psoriasis (N = 2) With Diabetes N = 39 With contraindication (CHF)N = 1 Without contraindication N = 38 Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Patient Populations

  18. Meta-analysis N = 42 trials Small trials (N=77-1549) Double-blind + open-label Follow-up (24-52 wks) N = 40 trials Large trials (N>4350) Double-blind Follow-up (3-5 yrs) N = 2 trials DREAM (N=5269) Impaired glucose tolerance ADOPT (N=4351) Newly diagnosed DM (<3 yrs) Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Trial Design

  19. Meta-analysis N = 42 trials RSG vs placebo N = 10 trials RSG vs standard Rx N = 32 trials • Add-on RSG vs placebo to • Run-in Rx (N = 28) • Metformin (N = 10) • Sulfonylurea (N = 12) • Insulin (N = 5) • Usual care (N = 1) • Head-to-head monotherapy (N = 4) • RSG vs Sulfonylurea (N = 3) • RSG vs Metformin/Sulfonylurea (N = 1) Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Treatment Groups

  20. Rosiglitazone and Cardiovascular Events Is There Heterogeneity? Absence of statistical heterogeneity does not imply absence of clinical heterogeneity

  21. Uncorrected (Peto) Corrected (MH/CC) 1.45 (0.88-2.39) Small trials combined (N=16391) 1.16 (0.76-1.78) DREAM (N=5269) ADOPT (N=4351) 1.43 (1.03-1.98) 1.28 (0.95-1.72) Overall pooled data (N=26011) 0 1 2 3 4 0 1 2 3 4 Odds ratio Odds ratio Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Myocardial Infarction

  22. Uncorrected (Peto) Corrected (MH/CC) Small trials combined (N=10825) 1.51 (0.82-2.78) 2.40 (1.17-4.91) DREAM (N=5269) ADOPT (N=4351) 1.33 (0.83-2.13) 1.64 (0.98-2.74) Overall pooled data (N=20445) 0 1 2 3 4 5 0 1 2 3 4 5 Odds ratio Odds ratio Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Cardiovascular Death

  23. Corrected (MH/CC) Uncorrected (Peto) 1.25 1.37 Diabetes (-CHF) (N=38) 2.69 Other diseases (N=4) 1.90 RSG vs placebo (N=10) 1.31 1.52 RSG vs antidiabetic Rx (N=32) 1.27 1.40 RSG + SULF vs SULF (N=12) 1.23 1.11 RSG + MET vs MET (N=10) 1.49 1.05 3.49 2.77 RSG + INS vs INS (N=5) 0 1 2 3 4 5 0 1 2 3 4 5 Odds Ratio Odds Ratio Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups MyocardialInfarction

  24. Corrected (MH/CC) Uncorrected (Peto) Diabetes (-CHF) (N=38) 1.34 1.58 Other diseases (N=4) 1.31 2.10 RSG vs placebo (N=10) 1.24 1.50 1.42 RSG vs antidiabetic Rx (N=32) 1.79 1.67 RSG + SULF vs SULF (N=12) 2.43 RSG + MET vs MET (N=10) 1.34 1.75 1.92 RSG + INS vs INS (N=5) 5.37 0 2 4 6 8 10 0 2 4 6 8 10 Odds Ratio Odds Ratio Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Cardiovascular Death

  25. Rosiglitazone and Cardiovascular Events Are the Risk Estimates Consistent? MyocardialInfarction/Ischemia GSK ICT analysis (N=42 trials) RECORD (N=4407) Balanced Cohort Study (N=33363) 0 1 2 3 Rate ratio Nonsignificantly increased odds ratio Cochrane Review (N=18 trials)

  26. Rosiglitazone and Cardiovascular Events Conclusions • Sensitive to meta-analytic method • Sensitive to continuity correction • Sensitive to subgroup analysis • If present, magnitude of harm is small We need more data!

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